Total Synthesis of an Exceptional Brominated 4‐Pyrone Derivative of Algal Origin: An Exercise in Gold Catalysis and Alkyne Metathesis

Abstract

A concise approach to the algal metabolite 1 is described, which also determines the previously unknown stereostructure of this natural product. Compound 1 is distinguished by a rare brominated 4-pyrone nucleus linked as a ketene–acetal to a polyunsaturated macrocyclic scaffold comprising an extra homoallylic bromide entity. The synthesis of 1 is based on the elaboration and selective functionalization of the linear precursor 23 endowed with no less than six different sites of unsaturation including the highly enolized oxo-alkanoate function. Key to success was the formation of the 2-alkoxy-4-pyrone ring by a novel gold-catalyzed transformation which engages only the acetylenic β-ketoester substructure of 23 but leaves all other π-bonds untouched. The synthesis was completed by a ring-closing alkyne metathesis to forge the signature cycloalkyne motif of 1 followed by selective bromination of the ketene–acetal site in the resulting product 27 without touching the skipped diene–yne substructure resident within the macrocyclic tether

Concise Total Synthesis of Ivorenolide B

“…In fact, complex 7 (and relatives) has proven itself in an umber of exigentc ases to be exquisitely selectivea nd functional group tolerant and might therefore be the catalyst of choice for the envisaged application. [10,26,[35][36][37][38][39] Treatmento f3a with an un-optimized 10 mol %l oading of 7 at ambient temperaturer esulted in smooth cyclization, furnishing the desired cyclodiyne 4 in 84 %y ield (entry 2). The reactionp roceeded www.chemeurj.org cleanly at ambient temperature, although the rate can be significantly increased upon gentle warming, without detriment to productivity (entry 3).…”

Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products

“…Thea bility of the gold complex as well as the alkyne metathesis catalyst to distinguish between different p-bonds while not inducing any scrambling was equally decisive in the total synthesis of the remotely related 4pyrone 31 (Scheme 13). [60] This unnamed compound, together with afew relatives,had also been isolated from red algae of the genus Phacelocarpus labellardieri. [61] Despite its remarkable structure,t he target had escaped total synthesis for decades.T he homoallylic bromide in the tether of 31 with latent "nonclassical" carbocation reactivity as well as the ketene-acetal moiety that links the tether to the heterocyclic…”

“…[54,56,65] To complete the total synthesis,t he resulting macrocycle 42 was brominated by exposure to NBS at what seems to be the most electron-rich position, namely the endocyclic keteneacetal site,togive syn-31 as the putative target. [60] The anti-configured isomer was prepared analogously. Whereas the spectroscopic data of syn-31 matched the reported data of the natural product very well, those of anti-31 showed significant deviations,w hich confirmed our biosynthetic hypothesis.…”

“…Whereas the spectroscopic data of syn-31 matched the reported data of the natural product very well, those of anti-31 showed significant deviations,w hich confirmed our biosynthetic hypothesis. [60] X-ray structure analysis showed that the macrocyclic ring of syn-31 adopts ap uckered conformation in the solid state.T his stereochemical feature likely explains why the skipped unsaturations,w hich had rendered all the intermediates starting from 37 exceedingly…”

Total Synthesis and Stereochemical Revision of Phacelocarpus 2‐Pyrone A

“…Indeed, no total synthesis of any membero ft his family had been completed since their isolation in the 1980s until earlier this year when the first synthesis of brominated ether 3 was reported by Fürstner's group. [3] Of particular notea mongstt his unusualf amily of compounds is phacelocarpus2 -pyrone A( 1), the only member to contain an unprecedented 2-pyronyl enol ether substructure as part of the skippedu nsaturated system.T he incorporation of these features into a1 9-membered macrocycle makes the construction of this compound af ormidable synthetic chal-lenge.T he structure of 1 was assignedo nt he basis of NMR spectroscopic data and also by comparison to compounds E-2 and Z-2,a nd the stereochemistry at the enol ether bond tentatively assigneda st he E-isomer. [1b] Since no total synthesis of 1 has thus far been reported,a nd following our recent successful completion of am odel compound, [4] we undertook to develop ac onvergent strategy for the synthesiso f1 to determine its authentic stereochemistry.Molecular modelsr evealedthat the macrocycle containing the E-vinyl ether was more strained than that containing the Zvinyl ether.D FT calculations (see the SupportingI nformation for methodology) indicate that the energy differenceb etween the E/Z stereoisomers is small and that both should therefore be viable.We anticipated that the major challenge in any synthetic route aimed towards 1 wouldb et he construction of the vinyl ether linked to the electron-withdrawing 2-pyrone motif.…”